Pharmaceutics

The management of rheumatoid arthritis and related inflammatory arthropathies is evolving from late structural assessment toward early molecular phenotyping of synovitis. Target-specific radiopharmaceuticals for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) now permit non-invasive detection of activated fibroblast-like synoviocytes, inflammatory macrophages, chemokine-driven immune-cell trafficking, angiogenesis, and mitochondrial stromal activation. This review analyzes the radiochemical basis of synovitis imaging, beginning with the radionuclide-dependent behavior of ¹¹C, ⁶⁸Ga, ⁶⁴Cu, [Al¹⁸F]²⁺, and ^99mTc, and then linking these properties to chelator selection, covalent radiolabeling, labeling conditions, and pharmacokinetics. The review further examines the development of radioligands targeting fibroblast activation protein (FAP), integrin α_vβ₃, folate receptor beta (β-FR), CXCR4, and the 18 kDa translocator protein (TSPO). It covers FAP-inhibitor scaffolds, RGD-based integrin probes, pteroyl-glutamate folate conjugates, CXCR4 antagonists, and TSPO heteroaromatic ligands. Clinical and translational datasets are discussed in relation to disease-activity evolution, treatment-response monitoring, and differentiation of stromal activation, macrophage infiltration, angiogenesis, and immune-cell recruitment. Finally, the review integrates kinetic modeling and dosimetric translation, emphasizing absorbed-dose estimation as a perspective on therapeutic optimization and safety constraints for emerging β-emitting and α-emitting synovial theranostics, ¹⁷⁷Lu and ²²⁵Ac. Collectively, these developments define a bench-to-bedside framework for rheumatology precision medicine, in which radiopharmaceutical chemistry, molecular imaging, clinical trial evidence, and patient-specific dosimetry converge to guide diagnosis, therapeutic selection, and future targeted synovial micro-radioresection.

Background/Objectives: Liquid self-nanoemulsifying drug delivery systems (L-SNEDDSs) efficiently improve oral bioavailability of poorly water-soluble drugs. However, adsorption onto mesoporous carriers often doubles the formulation mass and locks patients into multi-capsule regimens. This study aimed to develop a solid SNEDDS for glibenclamide (GLB), a weakly acidic, acid-labile, poorly soluble antidiabetic drug, using sodium carbonate as a multifunctional alkalizing excipient to enhance drug loading, improve chemical stability, and enable single-capsule administration. Methods: L-SNEDDSs were prepared using Tween 80, PEG 400, and Imwitor 308 (4:3:3, w/w). Sodium carbonate (Na₂CO₃) was benchmarked against triethanolamine as an alkalizing agent intended to promote in situ ionization (salt formation) of GLB. The optimized liquid was adsorbed onto Syloid (mesoporous silica) at a 1:1 (w/w) ratio to produce a free-flowing solid SNEDDS. Drug loading, dissolution, degradation kinetics at 40 °C and chemical stability at room temperature were evaluated. Results: Sodium carbonate incorporation significantly increased GLB solubility from 5.97 to 17.42 mg/g (2.9-fold increase, p < 0.01), outperforming triethanolamine (1.1-fold). The alkalized formulation extended the drug half-life at 40 °C from 12.4 to 30.1 days (2.4-fold, p < 0.01). Increasing drug loading in L-SNEDDSs from 5 to 15 mg/g maintained rapid in vitro dissolution, with >84% drug released within 10 min and similar dissolution efficiency (DE) across 5–15 mg/g despite tripling the drug content. The optimized solid (15 mg/g) achieved a 21.9-fold improvement in dissolution efficiency (p < 0.01) vs. raw drug. Moreover, it reduced total powder mass from 1000 to 333 mg and enabled single-capsule administration. Both liquid and solid alkalized SNEDDSs significantly enhanced GLB stability compared to the plain liquid SNEDDS. Conclusions: Overall, Na₂CO₃-enabled in situ ionization offers a practical, single-step approach to simultaneously mitigate poor solubility, acid-lability, and dose-volume limitations in solid SNEDDSs, providing a promising platform for improved oral delivery and potentially better patient adherence for weakly acidic, acid-labile drugs.

Objective: We aimed to develop and evaluate population pharmacokinetic (PopPK) models of atomoxetine incorporating clinically available patient information and to explore model-informed dose selection in Chinese children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: This retrospective single-center study included a model-building dataset of 102 patients (247 concentrations) and a patient-level holdout dataset of 65 patients (65 concentrations collected approximately 2 h post-dose). A one-compartment model with first-order absorption and elimination was developed. Body weight (BW) and alternative representations of CYP2D6 genetic information—rs1065852 genotype, activity score (AS), and predicted phenotype—were evaluated. Monte Carlo simulations evaluated steady-state 2 h post-dose concentrations (C_2h) across doses of 0.5–1.4 mg/kg/day; the model-informed dose was the lowest evaluated dose, achieving ≥75% probability of reaching the exploratory C_2h threshold of 268 ng/mL. Results: BW affected apparent clearance (CL/F) and volume of distribution, whereas rs1065852 genotype and AS additionally explained CL/F variability. In the holdout dataset, population predictions had limited bias (MdPE, 1.41–3.09%) but modest precision (MdAPE, 33.75–37.83%); CYP2D6-informed models improved selected performance measures. Simulation-derived doses ranged from 1.0 to 1.4 mg/kg/day across subgroups. No evaluated dose achieved the probability of target attainment (PTA) criterion for AS = 2 at any BW, or for the CC+CT and AS = 1.5 subgroups weighing 17–<30 kg. Alternative K_a assumptions changed median C_2h by at most 3.99% and PTA by 3.58 percentage points. Conclusions: BW and CYP2D6 genetic information explained part of atomoxetine pharmacokinetic variability and influenced simulated concentration attainment. These model-informed findings are exploratory and require prospective, multicenter validation against efficacy, tolerability, and safety outcomes before clinical implementation.